EP3427035B1 - Appareils microfluidiques - Google Patents

Appareils microfluidiques Download PDF

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Publication number
EP3427035B1
EP3427035B1 EP16910700.0A EP16910700A EP3427035B1 EP 3427035 B1 EP3427035 B1 EP 3427035B1 EP 16910700 A EP16910700 A EP 16910700A EP 3427035 B1 EP3427035 B1 EP 3427035B1
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EP
European Patent Office
Prior art keywords
fluid
chamber
microfluidic
property
controller
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EP16910700.0A
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German (de)
English (en)
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EP3427035A1 (fr
EP3427035A4 (fr
Inventor
Jeffrey A. Nielsen
Manish Giri
Chantelle Domingue
Kenneth Ward
Christie Dudenhoefer
Matthew David Smith
Joshua M. Yu
Hilary ELY
Diane R. HAMMERSTAD
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Hewlett Packard Development Co LP
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Hewlett Packard Development Co LP
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/1023—Microstructural devices for non-optical measurement
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/1031—Investigating individual particles by measuring electrical or magnetic effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1011—Control of the position or alignment of the transfer device
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016—Control of the volume dispensed or introduced
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1065—Multiple transfer devices
    • G01N35/1072—Multiple transfer devices with provision for selective pipetting of individual channels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1065—Multiple transfer devices
    • G01N35/1074—Multiple transfer devices arranged in a two-dimensional array
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/12—Specific details about manufacturing devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0663—Whole sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0883—Serpentine channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
    • B01L2400/0439—Moving fluids with specific forces or mechanical means specific forces vibrational forces ultrasonic vibrations, vibrating piezo elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1484—Optical investigation techniques, e.g. flow cytometry microstructural devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1034—Transferring microquantities of liquid
    • G01N2035/1041—Ink-jet like dispensers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1048—General features of the devices using the transfer device for another function
    • G01N2035/1062—General features of the devices using the transfer device for another function for testing the liquid while it is in the transfer device

Definitions

  • Microfluidics applies across a variety of disciplines including engineering, physics, chemistry, microtechnology and biotechnology. Microfluidics involves the study of small volumes, e.g., microliters, picoliters, or nanoliters, of fluid and how to manipulate, control and use such small volumes of fluid in various microfluidic systems and devices such as microfluidic devices or chips.
  • microfluidic biochips which may also be referred to as a "lab-on-chip" are used in the field of molecular biology to integrate assay operations for purposes such as analyzing enzymes and DNA, detecting biochemical toxins and pathogens, diagnosing diseases, etc.
  • US 2015/064694 discloses systems, including apparatus and methods, for the microfluidic manipulation, dispensing, and/or sorting of particles, such as cells and/or beads.
  • microfluidic apparatuses containing a microfluidic device or multiple microfluidic devices and methods for implementing the microfluidic device or devices.
  • a microfluidic system disclosed herein may also include the microfluidic apparatus or a plurality of similarly configured microfluidic apparatuses.
  • the microfluidic device includes a channel through which fluid from a fluid slot is to flow into a chamber (or equivalently, a foyer) from which the fluid may be dispensed through a nozzle in the foyer.
  • a sensor is be positioned to sense a property of a fluid passing through the channel.
  • a controller determines an electrical conductivity of the fluid, a property of a particle of interest, e.g., a cell, or the like, from signals received from the sensor.
  • the sensor may generate an electrical field through which the fluid may pass and the controller may determine a change in the electrical field, e.g., impedance, caused by the field passing through the electrical field.
  • the controller also determines whether the sensed property of the fluid meets a predetermined condition. In response to a determination that the sensed property of the fluid meets the predetermined condition, the controller performs a predefined action.
  • the predefined action may be a modification to a dispense protocol of a microfluidic system containing the microfluidic device.
  • fluid may be dispensed to desired locations based upon a sensed or detected property of the fluid.
  • the locations at which different fluids may be dispensed may depend upon the properties of the fluids.
  • the fluids may be dispensed to various locations through implementation of a closed-loop sensing and dispensing process.
  • the fluid may be dispensed in small quantities such as in microliter or picoliter volumes.
  • the particles of interest are cells, which are the basic structural and functional unit of an organism. Most animal and plant cells range in size from 1-100 micrometers and contain vital health information. In many instances, cell-based diagnostics are the gold standard for detecting infection diseases (HIV, Malaria, Tuberculosis), as well as chronic diseases (cancer, cardiac diseases, autoimmune diseases).
  • HIV infection diseases
  • Cancer cardiac diseases
  • autoimmune diseases a chronic disease 2019
  • FIG. 1A With reference first to FIG. 1A , there is shown a simplified block diagram of an example microfluidic apparatus 100. It should be understood that the microfluidic apparatus 100 depicted in FIG. 1A may include additional components and that some of the components described herein may be removed and/or modified without departing from a scope of the microfluidic apparatus 100 disclosed herein.
  • the microfluidic apparatus 100 is depicted as including a microfluidic device 102 and a controller 104.
  • the microfluidic device 102 is depicted as including a fluid slot 110 and a foyer 112, in which the foyer 112 is in fluid communication with the fluid slot 110 via a channel 114.
  • a portion of the fluid slot 110 is shown and may supply fluid to multiple microfluidic devices 102 housed in the microfluidic apparatus 100.
  • the channel 114 is depicted as having a smaller width than the foyer 112 such that the channel 114 may be considered as being pinched with respect to the foyer 112.
  • the channel 114 has been depicted as having a linear configuration, the channel 114 may include other shapes, such as a curved shape, a snake-like shape, a shape with corners, combinations thereof, or the like.
  • a sensor 116 is positioned to detect a property of a fluid flowing from the fluid slot 110 and into the foyer 112 through the channel 114.
  • the sensor 116 may detect a presence of a particle of interest, e.g., a cell or other particle, in the fluid as the fluid passes through the channel 114.
  • the fluid contained in the fluid slot 110 may be a host fluid having particles (e.g., a blood sample containing cells, an ink containing pigments/particles, or the like).
  • the sensor 116 may be an impedance sensor formed using semiconductor techniques and may be implemented using alternating current (AC) or direct current (DC) sensing.
  • the sensor 116 may detect impedance changes as particles in the fluid pass by the sensor 116 through the channel 114.
  • the sensor 116 may include metal electrodes that may form an electrical field through which the particles may pass.
  • the sensor 116 may include a photodetector, e.g., a laser source and a photodiode, and may detect cells or particles based upon detected changes in light.
  • the microfluidic device 102 is also depicted as including an actuator 118 and a nozzle 120 in fluid communication with the foyer 112. As shown, the actuator 118 is positioned in line with the nozzle 120. For instance, the actuator 118 may be positioned directly above or below the nozzle 120. In addition, activation of the actuator 118 may cause some of the fluid contained in the foyer 112 to be dispensed or expelled out of the microfluidic device 102 through the nozzle 120.
  • the structures and components of the microfluidic device 102 may be fabricated using integrated circuit microfabrication techniques such as electroforming, laser ablation, anisotropic etching, sputtering, dry and wet etching, photolithography, casting, molding, stamping, machining, spin coating, laminating, and the like.
  • the structures and components of the microfluidic device 102 may be formed of silicon.
  • the controller 104 may supply power, e.g., AC or DC, to the sensor 116 and may detect, based upon measurements obtained by the sensor 116, when a particle of interest, e.g., a cell, a particular type of cell, etc., has passed through the channel 114.
  • the sensor 116 may provide an electrical output signal representing the sensor data to the controller 104.
  • the controller 104 may activate the actuator 118 to expel fluid contained in the foyer 112 through the nozzle 120. In one regard, therefore, the controller 104 may control the actuator 118 in a closed-loop feedback manner based upon the detected particle of interest.
  • the actuator 118 may be a thermal resistor that produces vapor bubbles to create fluid displacement within the foyer 112.
  • the actuator 118 may be implemented as piezo elements (e.g., PZT) whose electrically induced deflections generate fluid displacements within the foyer 112.
  • the actuator 118 may be other types of deflective membrane elements activated by electrical, magnetic, and other forces.
  • the controller 104 may activate the actuator 118 a predefined number of times to expel the sensed particle of interest from the foyer 112 in instances in which less than all of the fluid contained in the foyer 112 is expelled during a single activation of the actuator 118.
  • the predefined number of times may correspond to the number of times that the actuator 118 is to be activated in order to expel most or all of the fluid contained in the foyer 112 immediately following detection of the particle of interest. That is, for instance, the predefined number of times may correspond to the number of times that the actuator 118 is to be activated in order to cause the particle of interest contained in the foyer 112 to be expelled.
  • the controller 104 may be a computing device, a semiconductor-based microprocessor, a central processing unit (CPU), an application specific integrated circuit (ASIC), and/or other hardware device.
  • the controller 104 may receive power from a power source or a power supply (not shown) and may supply AC or DC power to the sensor 116.
  • the microfluidic device 102 may be formed of a structural component 130, which may be formed of silicon, a polymeric material, an epoxy-based negative photoresist (such as SU-8), or the like.
  • the structural component 130 may be formed through implementation of microfabrication techniques such as electroforming, laser ablation, anisotropic etching, sputtering, dry and wet etching, photolithography, casting, molding, stamping, machining, spin coating, laminating, and the like.
  • the actuator 118 and the components of the sensor 116 may be formed into the structural component through integrated circuit fabrication techniques.
  • the channel 114 and the nozzle 120 may be formed through the structural component 130, for instance, by etching.
  • the channel 114 may have a cross-section that is sized such that a single particle, e.g., cell, may pass through the channel 114 at one time.
  • the channel 114 may be sized based upon the size of the particle 140 and may be slightly larger than the particle 140.
  • the channel 114 may have a height and a width that ranges from between about 5 microns and about 100 microns and a length that ranges from between about 5 microns and about 500 microns.
  • the term "about” may be defined as being between ⁇ 2 microns and ⁇ 100 microns.
  • the nozzle 120 may be sized such that fluid contained in the foyer 112 may substantially be prevented from unintentionally being dispensed through the nozzle 120. That is, for instance, the nozzle 120 may be sized such that surface tension of the fluid prevents the fluid from being expelled by gravitational forces while allowing a predetermined amount of fluid to be expelled when the actuator 118 is activated. In addition, the nozzle 120 may be sized such that a portion of the fluid contained in the foyer 112 may evaporate through the nozzle 120.
  • the controller 104 may supply power to the sensor 116, which may generate an electrical field 132.
  • the electrical field 132 may be disturbed.
  • the amount of disturbance, e.g., change in impedance, detected by the sensor 116 may vary depending upon the properties of the fluid, the type of particle 140 detected, etc. For instance, the amount of disturbance may vary for fluids having different electrical conductivity, light transmissivity, or other properties.
  • a first type of cell may cause a first change in impedance to be detected
  • a second type of cell may cause a second change in impedance to be detected, etc.
  • the senor 116 includes a light source and a photodetector
  • particles 140 having different characteristics may cause different changes in the detected light.
  • one of the sensor 116 elements may be provided on a top of the channel 114 and another one of the sensor 116 elements may be provided on a bottom of the channel 114.
  • the controller 104 may receive signals from the sensor 116 pertaining to the changes in the detected conditions. For instance, changes in the electrical field or the detected light as the fluid flows past the sensor 116 may cause changes in an electrical signal communicated to the controller 104.
  • the changes may include, for instance, changes in current and the controller 104 may determine changes in impedance from the received electrical signals.
  • the controller 104 may determine a sensed property of the fluid passing through the channel 114 from the received signals.
  • the controller 104 may determine the electrical conductivity of the fluid from the received electrical signals.
  • the controller 104 may determine the type of a particle detected in the channel 114 from the received electrical signals. In this example, the controller 104 may determine the type of the particle by comparing the received electrical signals, e.g., change in impedance levels, with the electrical signals of known particle types.
  • the controller 104 may also determine whether the sensed property of the fluid meets a predetermined condition and may perform a predefined action in response to the sensed property of the fluid meeting the predetermined condition.
  • the predetermined condition may be a predetermined electrical conductivity level of the fluid and the controller 104 may determine that the sensed property of the fluid meets the predetermined condition in response to the sensed electrical conductivity level of the fluid exceeding the predetermined electrical conductivity level.
  • the controller 104 may determine that the sensed property of the fluid fails to meet the predetermined condition in response to the sensed electrical conductivity level of the fluid falling below the predetermined electrical conductivity level.
  • the predetermined condition may be a predetermined type of particle, e.g., a predetermined type of cell.
  • the controller 104 may determine that the sensed property of the fluid meets the predetermined condition in response to the sensed property of the fluid indicating that a particle of the predetermined type has been detected. Likewise, the controller 104 may determine that the sensed property of the fluid fails to meet the predetermined condition in response to the sensed property of the fluid indicating that a particle of the predetermined type has not been detected.
  • the predefined action may include a protocol modification pertaining to dispensing of the fluid, e.g., a dispense protocol applied to the fluid contained in the foyer 112.
  • the protocol modification may include, for instance, changing a dispensing location of the fluid contained in the foyer 112, changing an order in which the fluid contained in the foyer 112 and another fluid contained in another foyer 112 are dispensed, changing a quantity of fluid dispensed into a well, dispensing a second fluid into a well into which the fluid was dispensed, dispensing the second fluid at a specific time following a determination that the sensed property of the fluid meets the predetermined condition, combinations thereof, or the like.
  • the controller 104 may activate the actuator 118 to cause fluid contained in the foyer 112 to be expelled through the nozzle 120 and/or may activate a second actuator to cause fluid contained in the foyer of another microfluidic device to be expelled.
  • the fluid contained in the foyer 112 may not be completely expelled when the actuator 118 is activated.
  • the controller 104 may cause the actuator 118 to be activated a predetermined number of times to cause all or substantially all of the fluid contained in the foyer 112 to be expelled.
  • the predetermined number of times may be equivalent to a number of times that may result in the clearing of the fluid contained in the foyer 112 to ensure that the particle of interest 140 is expelled from the foyer 112.
  • the controller 104 may cause the actuator 118 to be activated four times to ensure that the particle of interest is expelled from the foyer 112.
  • FIG. 2 there is shown a simplified cross-sectional side view of another example microfluidic device 200.
  • the microfluidic device 200 shown in FIG. 2 includes most of the same features as the microfluidic device 102 depicted in FIG. 1B and thus, common features will not be described in detail.
  • the microfluidic device 200 shown in FIG. 2 differs from the microfluidic device 102 depicted in FIG. 1B in that the sensor 116 elements are positioned outside of the channel 114. That is, one of the sensor 116 elements is depicted as being positioned at an inlet of the channel 114 and the other one of the sensor 116 elements is depicted as being positioned at an outlet of the channel 114.
  • FIG. 3 there is shown a simplified block diagram of another microfluidic apparatus 300.
  • the microfluidic apparatus 300 shown in FIG. 3 includes most of the same features as the microfluidic apparatus 100 depicted in FIG. 1A and thus, common features will not be described in detail.
  • the microfluidic apparatus 300 shown in FIG. 3 differs from the microfluidic apparatus 100 depicted in FIG. 1A in that the microfluidic device 302 includes different features as compared with the microfluidic device 102.
  • the microfluidic device 302 may include a second actuator 304 and a second nozzle 306.
  • the second actuator 304 may be positioned in-line with the second nozzle 306 and may be positioned on an opposite side of the foyer 112 with respect to the actuator 118.
  • the second actuator 304 may also be implemented as similar types of actuators as the actuator 118, e.g., thermal resistor, PZT, etc.
  • the controller 104 may control the second actuator 304, e.g., through a communication or signal line. That is, the controller 104 may supply energy to the second actuator 304 to cause the second actuator 304 to become activated and therefore cause some of the fluid contained in the foyer 112 to be expelled through the second nozzle 306. The controller 104 may activate the actuator 118 and the second actuator 304 in a sequence in response to a detection that a particle of interest has passed through the channel 114 and into the foyer 112.
  • controller 104 may activate the actuator 118 and the second actuator 304 a predetermined number of times until a volume of fluid equal to or substantially equal to the volume of fluid contained in the foyer 112 at the time the particle of interest was detected to have moved through the channel 114 has been expelled from the foyer 112.
  • the second nozzle 306 may function as a pressure relief during activation of the actuator 118 and the nozzle 120 may function as a pressure relief during activation of the second actuator 304. That is, when the actuator 118 (or the second actuator 304) is activated, pressure may be applied to the fluid contained in the foyer 112, which may cause some of the fluid to be forced back through the channel 114. A portion of the fluid contained in the foyer 112 may be expelled through the second nozzle 306 when the actuator 118 is activated to prevent the fluid from being forced back through the channel 114.
  • microfluidic devices 102 and 302 have been depicted as respectively having a single actuator 118 and two actuators 118, 302, it should be understood that the microfluidic devices 102, 302 disclosed herein may include a larger number of actuators and corresponding nozzles without departing from a scope of the present disclosure.
  • FIG. 4 there is shown a simplified block diagram of an example microfluidic system 400.
  • the microfluidic system 400 is depicted as including a plurality of microfluidic apparatuses 402-408, a substrate 410, and the controller 104.
  • Each of the microfluidic apparatuses 402-408 may be configured as shown in either of FIGS. 1A and 3 and may each contain a plurality of microfluidic devices.
  • the microfluidic devices may each be configured as shown in any of FIGS. 1A-3 .
  • each of the microfluidic apparatuses 402-408 may contain 6 or more microfluidic devices 102, 200, 302.
  • the substrate 410 is depicted as including a plurality of wells 412. According to an example, the substrate 410 may be movable in one dimension, two dimensions, or three-dimensions with respect to the microfluidic apparatuses 402-408.
  • the controller 104 may control a motor or other actuator to move the substrate 410 with respect to the microfluidic apparatuses 402-408. For instance, the controller 104 may cause the substrate 410 to be moved such that a particular well 412 is positioned beneath a particular one of the microfluidic apparatuses 402-408.
  • microfluidic apparatuses 402-408 different fluids may be inserted into each of the microfluidic apparatuses 402-408 and the controller 104 may individually control the microfluidic devices contained in the microfluidic apparatuses 402-408 to dispense the fluids into selected ones of the wells 412.
  • the controller 104 may control the microfluidic devices to dispense fluid containing particles, e.g., cells, into individual wells 412. That is, the controller 104 may control the dispensing of the fluid in the wells 412 depending upon the detected property of the fluid. For instance, the controller 104 may modify a dispensing protocol based upon the detected property of the fluid, in which the modification of the dispensing protocol may cause the fluid to be dispensed into a different well 412 than would occur under the unmodified dispensing protocol. The controller 104 may move the substrate 410 such that a different well 412 is positioned beneath the microfluidic apparatus 402 containing the microfluidic device in order to comply with the modified dispensing protocol.
  • FIG. 5 there is shown a simplified block diagram of an example microfluidic system 500. It should be understood that the microfluidic system 500 depicted in FIG. 5 may include additional components and that some of the components described herein may be removed and/or modified without departing from a scope of the microfluidic system 500 disclosed herein.
  • the microfluidic system 500 is shown as including a controller 502 and a data store 504.
  • the controller 502 may be the same as the controller 104 depicted in and described above with respect to FIG. 1A .
  • the controller 502 may thus be a computing device, a semiconductor-based microprocessor, a central processing unit (CPU), an application specific integrated circuit (ASIC), a programmable logic device (PLD), and/or other hardware device.
  • the controller 502 may also receive power from a power source or a power supply (not shown).
  • the data store 504 may be Random Access Memory (RAM), an Electrically Erasable Programmable Read-Only Memory (EEPROM), a storage device, an optical disc, or the like.
  • RAM Random Access Memory
  • EEPROM Electrically Erasable Programmable Read-Only Memory
  • the microfluidic system 500 may also include a computer readable storage medium 510 on which is stored machine readable instructions 512-516 that the controller 502 may execute. More particularly, the controller 502 may fetch, decode, and execute the instructions 512 to detect a property of a fluid passing through a channel 114. The controller 502 may fetch, decode, and execute the instructions 514 to determine whether the detected property meets a predefined condition. The controller 502 may fetch, decode, and execute the instructions 516 to perform a predefined action based upon whether the detected property meets a predefined condition. As an alternative or in addition to retrieving and executing instructions, the controller 502 may include one or more electronic circuits that include components for performing the functionalities of the instructions 512-516.
  • the computer readable storage medium 510 may be any electronic, magnetic, optical, or other physical storage device that contains or stores executable instructions.
  • the computer readable storage medium 510 may be, for example, Random Access Memory (RAM), an Electrically Erasable Programmable Read-Only Memory (EEPROM), a storage device, an optical disc, and the like.
  • RAM Random Access Memory
  • EEPROM Electrically Erasable Programmable Read-Only Memory
  • the computer readable storage medium 510 may be a non-transitory machine-readable storage medium, where the term "non-transitory" does not encompass transitory propagating signals.
  • the microfluidic system 500 may further include a plurality of microfluidic devices 520a-520n, in which the variable "n" represents an integer value greater than one.
  • Each of the microfluidic devices 520a-520n may be similar to one of the microfluidic devices 102, 200, 300 depicted in FIGS. 1A-3 .
  • the microfluidic devices 520a-520n may each include a sensor 522a-522n and an actuator 524a-524n.
  • the microfluidic devices 520a-520n may each include multiple actuators 524n.
  • the microfluidic devices 520a-520n may include multiple sensors 522a-522n.
  • the microfluidic devices 520a-520n are housed in a single microfluidic apparatus.
  • a first group of the microfluidic devices 520a-520n is housed in a first microfluidic apparatus and a second group of the microfluidic devices 520a-520n is housed in a second microfluidic apparatus.
  • the microfluidic system 500 may further include a substrate 530, which may be similar to the substrate 410 depicted in FIG. 4 .
  • the controller 502 may control the substrate 530 such that selected wells 412 may be positioned to receive fluid from the desired ones of the microfluidic devices 520a-520n.
  • FIGS. 6 and 7 depict example methods 600 and 700 for dispensing fluid through a microfluidic device. It should be apparent to those of ordinary skill in the art that the methods 600 and 700 may represent generalized illustrations and that other operations may be added or existing operations may be removed, modified, or rearranged without departing from the scopes of the methods 600 and 700.
  • a detection may be made, at a channel 114 of a microfluidic device 520a, of a property of a fluid passing through the channel 114 into a foyer 112 of the microfluidic device 520a.
  • the controller 502 may execute the instructions 512 to detect a property of the fluid using signals received from a sensor 116 located near the channel 114.
  • the detected property may include, for instance, an electrical conductivity of the fluid, a light transmissivity of the fluid, whether a particle of interest 140 is contained in the fluid passing through the channel 114, or the like.
  • the controller 502 may receive electrical signals from the sensor 116, e.g., from electrodes, photodiodes, etc., of the sensor 116, and may detect the property of the fluid from the received electrical signals.
  • the sensor 116 may include a processor than may detect the property and may communicate the detected property to the controller 502.
  • the controller 502 may determine whether the detected property of the fluid meets a predetermined condition. For instance, the controller 502 may execute the instructions 514 to make this determination.
  • the predetermined condition may be a predetermined electrical conductivity level of the fluid and the controller 502 may determine that the sensed property of the fluid meets the predetermined condition in response to the sensed electrical conductivity level of the fluid exceeding the predetermined electrical conductivity level. Likewise, the controller 502 may determine that the sensed property of the fluid fails to meet the predetermined condition in response to the sensed electrical conductivity level of the fluid falling below the predetermined electrical conductivity level.
  • the predetermined condition may be a predetermined type of particle, e.g., a predetermined type of cell.
  • the controller 502 may determine that the sensed property of the fluid meets the predetermined condition in response to the sensed property of the fluid indicating that a particle of the predetermined type has been detected. Likewise, the controller 502 may determine that the sensed property of the fluid fails to meet the predetermined condition in response to the sensed property of the fluid indicating that a particle of the predetermined type has not been detected.
  • the controller 502 may modify a dispense protocol of the microfluidic system 500.
  • the controller 502 may execute the instructions 516 to perform a predefined action on the fluid contained in the foyer 112 in response to the detected property of the fluid meeting the predetermined condition.
  • the controller 502 may activate an actuator 118 or multiple actuators 118, 304 in one microfluidic device 520a or multiple microfluidic devices 520a-520n to dispense a fluid or multiple fluids into wells 412 of the substrate 530 or other target locations.
  • the controller 502 may activate the actuator(s) 118 a predetermined number of times to evacuate a predefined volume of fluid through a nozzle 120 from the foyer 112, in which the predefined volume of fluid is equivalent or nearly equivalent to a total volume of fluid contained in the foyer 112 prior to the foyer 112 being refilled with additional fluid.
  • the predefined action may include a protocol modification pertaining to dispensing of the fluid, e.g., a dispense protocol applied to the fluid contained in the foyer 112.
  • the protocol modification may include, for instance, changing a dispensing location of the fluid contained in the foyer 112, changing an order in which the fluid contained in the foyer 112 and another fluid contained in another foyer 112 are dispensed, changing a quantity of fluid dispensed into a well, dispensing a second fluid into a well into which the fluid was dispensed, dispensing the second fluid at a specific time following a determination that the sensed property of the fluid meets the predetermined condition, combinations thereof, or the like.
  • the controller 502 may activate the actuator 118 to cause fluid contained in the foyer 112 to be expelled through the nozzle 120 and/or may activate a second actuator to cause fluid contained in the foyer of another microfluidic device to be expelled.
  • power may be applied to a sensor 522a or to multiple sensors 522a-522n.
  • the controller 502 may supply power to the sensor(s) 522a-522n such that the sensor(s) 522a-522n generate an electric field or other detection field, e.g., a laser beam and photodetector.
  • the sensor(s) 522a-522n may be positioned to detect a property of a fluid as the fluid flows through a channel 114 of a microfluidic device 102, 200, 302 or multiple channels 114of multiple microfluidic devices 102, 200, 302.
  • the controller 502 may receive signals from the sensor(s) 522a-522n. For instance, the controller 502 may receive electrical signals from the electrodes of the sensor(s) 522a-522n. In another example, the controller 502 may receive electrical signals from a photodiode of the sensor(s) 522a-522n. In a yet further example in which the sensor(s) 522a-522n includes a processor, the controller 502 may receive detected information, such as detected current changes, detected electrical field strength changes, detected impedance information, information pertaining to changes in light detected by a photodetector, or the like.
  • detected information such as detected current changes, detected electrical field strength changes, detected impedance information, information pertaining to changes in light detected by a photodetector, or the like.
  • the controller 502 may detect a property of the fluid from the received signals. That is, the controller 502 may detect a property of the fluid as the fluid flows through the channel 114 and into the foyer 112. As discussed herein, the detected property of the fluid may include, for instance, a detected electrical conductivity level, light transmissivity level, detected particle property, or the like.
  • the controller 502 may determine whether the detected property of the fluid meets a predetermined condition. For instance, the controller 502 may determine whether a detected particle has an electrical signature that matches a predetermined electrical signature, e.g., the detected particle causes a change in a detected impedance to vary by a predetermined amount. As another example, the controller 502 may determine whether the electrical conductivity of the fluid exceeds a predetermined electrical conductivity level.
  • the controller 502 may continue to receive signals from the sensor(s) 522a-522n at block 704, continue to detect a property of the fluid from the received signals at block 706, and continue to determine whether the detected property meets the predetermined condition at block 708. However, in response to a determination at block 708 that the detected property does meet the predetermined condition, the controller 502 may modify a dispense protocol of the microfluidic system 500 as indicated at block 710.
  • the controller 502 may modify the dispense protocol in response to the detected property meeting the predetermined condition such that the fluid contained in the foyer 112 is dispensed into a different well.
  • the controller 502 may implement the modified dispense protocol. For instance, the controller 502 may change a dispensing location of the fluid contained in the foyer 112, change an order in which the fluid contained in the foyer 112 and another fluid contained in another foyer 112 are dispensed, change a quantity of fluid dispensed into a well, dispense a second fluid into a well into which the fluid was dispensed, dispense the second fluid at a specific time following a determination that the sensed property of the fluid meets the predetermined condition, combinations thereof, or the like.
  • the controller 502 may activate the actuator 118 to cause fluid contained in the foyer 112 to be expelled through the nozzle 120 and/or may activate a second actuator to cause fluid contained in the foyer of another microfluidic device to be expelled.
  • the controller 502 may determine whether to continue the method 700.
  • the controller 502 may determine that the method 700 is to be continued in response to a determination that an additional fluid is to be delivered into a well 412.
  • the controller 502 may repeat blocks 704-714 until the controller 140 determines that the method 700 is to end.
  • the controller 140 may stop supplying power to the sensor(s) 522a-522n as indicated at block 716.
  • the controller 502 may end the method 700 as indicated at block 718.
  • fluids and/or particles of interest may be dispensed into desired locations, e.g., wells 412 in a substrate 410, based upon detected properties of the fluids and/or particles of interest.
  • the methods 600 and 700 may enable for closed-loop control of fluid dispending based upon the detected properties.
  • Some or all of the operations set forth in the methods 600 and 700 may be contained as programs or subprograms, in any desired computer accessible medium.
  • the methods 600 and 700 may be embodied by computer programs, which may exist in a variety of forms both active and inactive. For example, they may exist as machine readable instructions, including source code, object code, executable code or other formats. Any of the above may be embodied on a non-transitory computer readable storage medium.
  • non-transitory computer readable storage media include computer system RAM, ROM, EPROM, EEPROM, and magnetic or optical disks or tapes. It is therefore to be understood that any electronic device capable of executing the above-described functions may perform those functions enumerated above.

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Claims (15)

  1. Appareil microfluidique (100, 300, 402, 404, 406, 408) comprenant :
    un dispositif microfluidique (102) comprenant :
    un canal (114) ;
    une chambre (112), dans lequel la chambre est en communication fluidique avec le canal et dans lequel le canal a une largeur plus petite que la chambre ;
    un capteur (116, 522) pour détecter une propriété d'un fluide passant à travers le canal dans la chambre (112) ;
    une buse (120) en communication fluidique avec la chambre ;
    un actionneur (118, 524) positionné en ligne avec la buse et servant à distribuer moins de la totalité d'un fluide contenu dans la chambre (112) à travers la buse (120) dans des puits d'un substrat ou d'un autre emplacement cible ; et
    un dispositif de commande (104, 502) configuré pour déterminer si la propriété détectée du fluide remplit une condition prédéterminée et pour effectuer une action prédéfinie sur le fluide contenu dans la chambre en réponse à la propriété détectée du fluide remplissant la condition prédéterminée.
  2. Appareil microfluidique selon la revendication 1, comprenant en outre une seconde chambre et un second fluide, dans lequel l'action prédéfinie comprend au moins un élément parmi le changement d'un emplacement de distribution du fluide contenu dans la chambre, le changement d'un ordre dans lequel le fluide contenu dans la chambre et le second fluide contenu dans la seconde chambre doivent être distribués, le changement d'une quantité de fluide devant être distribuée dans un puits, la distribution du fluide dans un puits et la distribution du second fluide de la seconde chambre dans le puits dans lequel le fluide a été distribué, et la distribution du second fluide à un moment spécifique après une détermination que la propriété détectée du fluide remplit la condition prédéterminée.
  3. Appareil microfluidique selon la revendication 1, dans lequel le dispositif de commande est configuré pour effectuer l'action prédéfinie en modifiant un protocole de distribution appliqué au fluide contenu dans la chambre.
  4. Appareil microfluidique selon la revendication 1, dans lequel la propriété du fluide est une conductivité électrique du fluide.
  5. Appareil microfluidique selon la revendication 1, dans lequel la propriété du fluide est un type prédéterminé de particule contenue dans le fluide.
  6. Appareil microfluidique selon la revendication 1, comprenant en outre :
    une seconde chambre contenant un second fluide ;
    une seconde buse ; et
    un second actionneur, dans lequel le dispositif de commande doit activer le second actionneur pour amener un second fluide dans la seconde chambre à être distribué à travers la seconde buse en réponse à la propriété détectée du fluide remplissant la condition prédéterminée.
  7. Appareil microfluidique selon la revendication 1, comprenant en outre :
    un substrat contenant une pluralité de puits, dans lequel le dispositif de commande est configuré pour commander l'actionneur pour amener un fluide dans la chambre à être distribué à travers la buse et dans un premier puits de la pluralité de puits en réponse au fait que la propriété détectée du fluide remplit la condition prédéterminée et pour commander l'actionneur pour amener un fluide dans la chambre à être distribué à travers la buse et dans un second puits de la pluralité de puits en réponse au fait que la propriété détectée du fluide ne remplit pas à la condition prédéterminée.
  8. Appareil microfluidique selon la revendication 1, comprenant en outre :
    une pluralité de dispositifs microfluidiques, dans lequel chaque dispositif de la pluralité de dispositifs microfluidiques comprend :
    une chambre en communication fluidique avec un canal ayant une section transversale plus petite que la chambre ;
    un capteur pour détecter une propriété d'un fluide passant à travers le canal et dans la chambre ;
    une buse en communication fluidique avec la chambre ;
    un actionneur positionné en ligne avec la buse et servant à amener moins de la totalité du fluide contenu dans la chambre (112) à être expulsé à travers la buse (120) ; et
    dans lequel le dispositif de commande est configuré pour modifier un protocole de distribution appliqué à la pluralité de dispositifs microfluidiques sur la base des propriétés détectées du fluide passant à travers les canaux.
  9. Appareil microfluidique selon la revendication 8, dans lequel le dispositif de commande est configuré pour modifier le protocole de distribution par au moins un élément parmi le changement d'un emplacement de distribution du fluide contenu dans la chambre, le changement d'un ordre dans lequel le fluide contenu dans la chambre et un autre fluide contenu dans une autre chambre sont distribués, le changement d'une quantité de fluide distribuée dans un puits, la distribution d'un second fluide dans un puits dans lequel le fluide a été distribué, et la distribution du second fluide à un moment spécifique après une détermination que la propriété détectée du fluide remplit la condition prédéterminée.
  10. Appareil microfluidique selon la revendication 8, dans lequel le dispositif de commande est en outre configuré pour activer l'actionneur dans un premier dispositif microfluidique de la pluralité de dispositifs microfluidiques en réponse à une détermination que la propriété détectée d'un fluide passant à travers le canal dans un second dispositif microfluidique de la pluralité de dispositifs microfluidiques remplit une condition prédéterminée.
  11. Procédé de fonctionnement de l'appareil microfluidique selon la revendication 1, le procédé comprenant :
    la détection, au niveau du canal du dispositif microfluidique, d'une propriété d'un fluide passant à travers le canal dans la chambre du dispositif microfluidique ;
    la détermination établissant si la propriété détectée du fluide remplit une condition prédéterminée ; et
    en réponse à une détermination que la propriété détectée du fluide remplit la condition prédéterminée, la réalisation d'une action prédéfinie sur le fluide contenu dans la chambre.
  12. Procédé selon la revendication 11, dans lequel l'appareil microfluidique comprend en outre une seconde chambre et un second fluide, et dans lequel la réalisation de l'action prédéfinie sur le fluide contenu dans la chambre comprend en outre au moins un élément parmi le changement d'un emplacement de distribution du fluide contenu dans la chambre, le changement d'un ordre dans lequel le fluide contenu dans la chambre et le second fluide contenu dans la seconde chambre doivent être distribués, le changement d'une quantité de fluide devant être distribuée dans un puits, la distribution du fluide dans un puits et la distribution du second fluide dans le puits dans lequel le fluide a été distribué, et la distribution du second fluide à un moment spécifique après une détermination que la propriété détectée du fluide remplit la condition prédéterminée.
  13. Procédé selon la revendication 8, dans lequel la détection de la propriété du fluide passant à travers le canal dans la chambre comprend en outre la détection d'une conductivité électrique du fluide passant à travers le canal.
  14. Procédé selon la revendication 8, dans lequel la détection de la propriété du fluide passant à travers le canal dans la chambre comprend en outre la détection d'un signal électrique d'une particule dans le fluide passant à travers le canal.
  15. Procédé selon la revendication 8, comprenant en outre :
    l'activation d'un second actionneur en réponse à une détermination établissant que la propriété détectée du fluide remplit la condition prédéterminée, dans lequel l'activation du second actionneur amène un second fluide contenu dans une seconde chambre à être distribué à travers une seconde buse.
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US11203017B2 (en) 2021-12-21
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CN109313117A (zh) 2019-02-05
CN109313117B (zh) 2022-01-14
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EP3427035A4 (fr) 2019-05-08
WO2018022025A1 (fr) 2018-02-01

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